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Anti-cancer drug combinations approved by US FDA from 2011 to 2021: main design features of clinical trials and role of pharmacokinetics

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Abstract

During the last decade, the treatment for many cancer indications has evolved due to intensive clinical research into anti-tumor agents’ combination. In most instances, new combination treatments consist of an add-on to the standard of care (SOC), which then demonstrate a substantial gain in efficacy and no detrimental effect in tolerability. In the era of targeted therapies, for which maximum tolerated dose (MTD)-based dosing strategies are no longer applicable, early stage studies exploring new combinations are often conducted in the population of interest, expediting the collection of preliminary safety data, to be promptly expanded to collect preliminary efficacy data. Nevertheless, rule-based dose-finding studies are still a prevailing approach for early stage cancer, especially for chemotherapy (CT)-containing combinations. Pharmacokinetic (PK) assessments play a key role throughout the clinical development of drug combinations, informing potential PK interactions. But most importantly, they allow the development of innovative exposure–response (E–R) models aimed at exploring the contribution of each agent to the overall effect of the combination therapy. This review identifies 81 new drug combinations approved by the United States Food and Drug Administration (FDA) for hemato-oncology during the 2011–2021 period and summarizes the main design features of clinical trials and the role of PK assessments.

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Authors and Affiliations

  1. Pharma Mar S.A, Avda. de los Reyes, 1, Polígono Industrial “La Mina”, 28770, Colmenar Viejo (Madrid, Spain

    Salvador Fudio, Alvaro Sellers, Laura Pérez Ramos, Ali Zeaiter & Rubin Lubomirov

  2. Healthcotrials, Madrid, Spain

    Beatriz Gil-Alberdi

  3. Clinical Pharmacology Department, La PAZ University Hospital-Idipaz, Universidad Autónoma DE Madrid, Madrid, Spain

    Mikel Urroz & Antonio Carcas

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Contributions

SF and RL contributed to conception and design of the review. AS helped with the literature search and organization. AS, MU, and AC contributed to data extraction. SF wrote the manuscript. LPR drew the figures. BGA contributed with a critical assessment, and editorial review of the manuscript. AZ contributed with a critical assessment and expert review. All authors contributed to manuscript revision. All authors read and approved the final manuscript.

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Correspondence to Rubin Lubomirov.

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Fudio, S., Sellers, A., Pérez Ramos, L. et al. Anti-cancer drug combinations approved by US FDA from 2011 to 2021: main design features of clinical trials and role of pharmacokinetics. Cancer Chemother Pharmacol 90, 285–299 (2022). https://doi.org/10.1007/s00280-022-04467-7

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